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Last season's gallant beaten finalists Bradford City fell in the first round of the League Cup on Tuesday, while there were shock exits for four Championship teams.
Bradford sensationally beat Arsenal, Aston Villa and Wigan Athletic en route to February's Wembley final, where they lost to Swansea City, but the third-tier side stumbled at the first hurdle this season after losing 2-1 at Huddersfield Town.
Newport County of fourth-tier League Two pulled off the biggest upset of the night by recording a 3-1 extra-time win at Brighton and Hove Albion, who reached last season's Championship play-off semi-finals.
Welsh side Newport only returned to the Football League this year after 25 years in the non-league wilderness.
Brighton's second-tier counterparts Middlesbrough, Ipswich Town and Sheffield Wednesday also tasted defeat in the opening round.
League Two Accrington Stanley, now coached by former England striker James Beattie, pulled off a 2-1 win over Middlesbrough at the Riverside Stadium.
Ipswich fell 2-0 at third-division Stevenage, while Wednesday lost 2-1 at local rivals Rotherham United.
Championship favourites Queens Park Rangers enjoyed a more straightforward outing, with new signing Charlie Austin netting an early opener in a 2-0 success at Exeter City.
However, there was fresh misery for fallen giants Wolverhampton Wanderers, relegated to the third tier last season, as they lost 1-0 at Morecambe via a fine free-kick from Ryan Williams in the 84th minute.