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Manchester City dashed the dreams of Salford's former Manchester United star owners with an 8-0 FA Cup rout on Saturday, while Liverpool cruised into the fourth round with a 4-0 victory over Accrington Stanley.
Chelsea were among the other big winners with a 5-0 demolition of Morecambe.
Brentford were the only Premier League side to fall to lower-league opposition as Plymouth, who sit bottom of the Championship, stunned the Bees 1-0 thanks to Morgan Whittaker's late winner.
League Two Salford have risen through the non-league ranks since investment from David Beckham, Gary and Phil Neville, Paul Scholes, Ryan Giggs and Nicky Butt began in 2014.
Scholes, Butt and director of football Giggs were in attendance at the Etihad but were denied a night to rival their best during glorious playing careers at Old Trafford.
Pep Guardiola made wholesale changes as Erling Haaland was afforded a rest.
Jeremy Doku opened the scoring after just eight minutes before youngsters Divin Mubama and Nico O'Reilly made it 3-0 before half-time.
Jack Grealish scored his first City goal for over a year from the penalty spot, while Doku also netted from the spot.
But James McAtee, who had only scored once for City previously, earned man-of-the-match with a 20-minute second half hat-trick.
- Alexander-Arnold leads by example -
There was never any hint of an upset at Anfield either despite Arne Slot making eight changes for Liverpool.
Trent Alexander-Arnold was named captain in the absence of Virgil van Dijk and led by example after being criticised for his display in a 2-2 draw against Manchester United last weekend.
Slot had warned the Premier League leaders that a trip to Anfield would be Accrington's "Champions League final".
A mammoth 86 league positions behind Liverpool in the 92-team English league system, Stanley held out for nearly half an hour before Diogo Jota was left with a simple task to tap in from Darwin Nunez's low cross.
Alexander-Arnold then stepped forward to double the lead with a sumptuous hit into the top corner from outside the box.
"I could talk for hours about that (goal), unbelievable," said Slot said.
"The biggest compliment Trent could get was the reaction of everyone after the Manchester United game.
"Every player around the world, maybe except for a few, has a bad game and that is completely normal, but the moment Trent has one, everyone has an opinion about it."
Jayden Danns made it 3-0 before Federico Chiesa netted his first Liverpool goal after an injury-hit start to his time in England.
Joao Felix was the star of the show for Chelsea as he got a rare chance to deputise for Cole Palmer.
The Portuguese international and Tosin Adarabioyo both scored twice, while Christopher Nkunku made up for missing an early penalty by netting his 13th goal of the season.
- Brentford stung -
Only Liverpool have taken more points at home than Brentford in the Premier League this season, while Plymouth had not won away from home all campaign.
Yet against the odds Argyle, who sacked former England captain Wayne Rooney 12 days ago, held out and hit Thomas Frank's men with a sucker punch when Whittaker blasted in from outside the area nine minutes from time.
"I have pride in everybody, and I'm pleased for the supporters. It's a big day for us," said caretaker Plymouth boss Kevin Nancekivell.
"The FA Cup brings that romance and we've put a little bit of history in it today by getting the win."
High-flying Nottingham Forest continued their excellent season with a comfortable 2-0 win over Luton.
Brighton were 4-0 winners at Norwich as Georginio Rutter struck twice.
Bournemouth shrugged off the loss of strikers Evanilson and Enes Unal to long-term injuries this week to roar back from 1-0 down to hammer West Brom 5-1.
Leicester went one better by hitting QPR for six in an eight-goal thriller at the King Power.
Wolves' bright start under new boss Vitor Pereira continued as early goals from Rayan Ait-Nouri and Rodrigo Gomes secured a 2-1 win at Bristol City.
S.Jones--TFWP